The six "internal" genes of the avian influenza A/Mallard/6750/78 virus reproducibly attenuated three human influenza A viruses belonging to two different antigenic subtypes. Infection with one of the avian-human influenza A reassortant viruses induced resistance to challenge with homologous wild type virus. Two avian-human influenza A reassortant viruses derived from the avian influenza A/Pintail/79 virus were overattenuated for volunteers. The PA polymerase gene of the influenza A/Ann Arbor/6/60 cold-adapted (ca) donor virus appears to play a major role in the attenuation of human influenza A viruses. A "six-gene" ca reassortant virus can infect and induce protective levels of immunity in over half of seropositive and about 90% of seronegative volunteers. The ca reassortant vaccines induce resistance to homologous wild type virus challenge that persists seven months post-vaccination at a level slightly greater than that induced by inactivated vaccine. However, ca reassortant immunity does wane by seven months as indicated by a partial loss of protection against infection and upper respiratory tract illness. This decrease in resistance correlates with a three-fold decrease in the level of nasal wash IgA antibody. The mediators of immunity induced by inactivated vaccine are serum HAI antibody, serum NI antibody, and nasal wash IgG HA antibody. The mediators of immunity induced by infection with ca vaccines are serum NI, and nasal wash IgA HA antibody.